Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer's disease-relevant tau constructs in organotypic hippocampal slices

Alzheimer's disease (AD) is characterized by progressive loss of neurons in selected brain regions, extracellular accumulations of amyloid beta, and intracellular fibrils containing hyperphosphorylated tau. Tau mutations in familial tauopathies confirmed a central role of tau pathology; however, the role of tau alteration and the sequence of tau-dependent neurodegeneration in AD remain elusive. Using Sindbis virus-mediated expression of AD-relevant tau constructs in hippocampal slices, we show that disease-like tau modifications affect tau phosphorylation at selected sites, induce Alz50/MC1-reactive pathological tau conformation, cause accumulation of insoluble tau, and induce region-specific neurodegeneration. Live imaging demonstrates that tau-dependent degeneration is associated with the development of a "ballooned" phenotype, a distinct feature of cell death. Spine density and morphology is not altered as judged from algorithm-based evaluation of dendritic spines, suggesting that synaptic integrity is remarkably stable against tau-dependent degeneration. The data provide evidence that tau-induced cell death involves apoptotic as well as nonapoptotic mechanisms. Furthermore, they demonstrate that targeted expression of tau in hippocampal slices provides a novel model to analyze tau modification and spatiotemporal dynamics of tau-dependent neurodegeneration in an authentic CNS environment

Revealing oft-cited but unpublished papers of Colin Pittendrigh and coworkers

Among the scientific resources that Colin Pittendrigh passed on to his colleagues after his death in 1996 were two unpublished papers. These manuscripts, developed first in the mid-1960s and continually updated and refined through the late 1970s, centered on the development and experimental exploration of a model of circadian entrainment combining aspects of the well-known parametric (continuous) and nonparametric (discrete) models of entrainment. These texts reveal the experimental work surrounding Pittendrigh's determination of the limits of entrainment and the explanation of the bistability phenomenon. These manuscripts are being made publicly available in their final format (February 1978) as supplementary material to this introduction

Фізико-хімічна геотехнологія

Розглянуто принципові засади геотехнологічного видобування різнома- нітних корисних копалин. Викладено питання розкриття та підготовки родовищ за допомогою свердловинної розробки, проаналізовано способи буріння і кріп- лення геотехнологічних свердловин, а такж застосоване обладнання. Розкрито сутність технологічних процесів, які виконуються при диспергуванні гірських порід, розчиненні солей, вилуговуванні металів, підземній виплавці сірки і га- зифікації вугілля, видобуванні в’язкої нафти та сланцьового газу. Навчальний посібник призначений для студентів, які навчаються за спе- ціальністю «Розробка родовищ та видобування корисних копалин», а також для студентів інших спеціальностей гірничих вузів і факультетів та інженерно- технічних працівників підприємств і проектних організацій гірничовидобувних галузей промисловості України

Neonicotinoids Disrupt Circadian Rhythms and Sleep in Honey Bees

Honey bees are critical pollinators in ecosystems and agriculture, but their numbers have significantly declined. Declines in pollinator populations are thought to be due to multiple factors including habitat loss, climate change, increased vulnerability to disease and parasites, and pesticide use. Neonicotinoid pesticides are agonists of insect nicotinic cholinergic receptors, and sub-lethal exposures are linked to reduced honey bee hive survival. Honey bees are highly dependent on circadian clocks to regulate critical behaviors, such as foraging orientation and navigation, time-memory for food sources, sleep, and learning/memory processes. Because circadian clock neurons in insects receive light input through cholinergic signaling we tested for effects of neonicotinoids on honey bee circadian rhythms and sleep. Neonicotinoid ingestion by feeding over several days results in neonicotinoid accumulation in the bee brain, disrupts circadian rhythmicity in many individual bees, shifts the timing of behavioral circadian rhythms in bees that remain rhythmic, and impairs sleep. Neonicotinoids and light input act synergistically to disrupt bee circadian behavior, and neonicotinoids directly stimulate wake-promoting clock neurons in the fruit fly brain. Neonicotinoids disrupt honey bee circadian rhythms and sleep, likely by aberrant stimulation of clock neurons, to potentially impair honey bee navigation, time-memory, and social communication

Large-scale filaments associated with Milky Way spiral arms

The ubiquity of filamentary structure at various scales through out the Galaxy has triggered a renewed interest in their formation, evolution, and role in star formation. The largest filaments can reach up to Galactic scale as part of the spiral arm structure. However, such large scale filaments are hard to identify systematically due to limitations in identifying methodology (i.e., as extinction features). We present a new approach to directly search for the largest, coldest, and densest filaments in the Galaxy, making use of sensitive Herschel Hi-GAL data complemented by spectral line cubes. We present a sample of the 9 most prominent Herschel filaments, including 6 identified from a pilot search field plus 3 from outside the field. These filaments measure 37-99 pc long and 0.6-3.0 pc wide with masses (0.5-8.3)$\times10^4 \, M_\odot$, and beam-averaged ($28"$, or 0.4-0.7 pc) peak H$_2$ column densities of (1.7-9.3)$\times 10^{22} \, \rm{cm^{-2}}$. The bulk of the filaments are relatively cold (17-21 K), while some local clumps have a dust temperature up to 25-47 K. All the filaments are located within <~60 pc from the Galactic mid-plane. Comparing the filaments to a recent spiral arm model incorporating the latest parallax measurements, we find that 7/9 of them reside within arms, but most are close to arm edges. These filaments are comparable in length to the Galactic scale height and therefore are not simply part of a grander turbulent cascade.Comment: Published 2015MNRAS.450.4043W; this version contains minor proof corrections. FT-based background removal code at https://github.com/esoPanda/FTbg SED fitting code at http://hi-gal-sed-fitter.readthedocs.org 3D interactive visualization at http://www.eso.org/~kwan

Unveiling the Early-Stage Anatomy of a Protocluster Hub with ALMA

High-mass stars shape the interstellar medium in galaxies, and yet, largely because the initial conditions are poorly constrained, we do not know how they form. One possibility is that high-mass stars and star clusters form at the junction of filamentary networks, referred to as "hubs". In this letter we present the complex anatomy of a protocluster hub within an Infrared Dark Cloud (IRDC), G035.39-00.33, believed to be in an early phase of its evolution. We use high-angular resolution ($\{\theta_{\rm maj}, \theta_{\rm min}\}=\{1.''4, 0.''8\}\sim\{0.02\,{\rm pc}, 0.01\,{\rm pc}\}$) and high-sensitivity ($0.2$ mJy beam$^{-1}$; $\sim0.2$ M$_{\odot}$) 1.07 mm dust continuum observations from the Atacama Large Millimeter Array (ALMA) to identify a network of narrow, $0.028\,\pm\,0.005$ pc wide, filamentary structures. These are a factor of $\gtrsim3$ narrower than the proposed "quasi-universal" $\sim0.1$ pc width of interstellar filaments. Additionally, 28 compact objects are reported, spanning a mass range $0.3\,{\rm M_{\odot}}<M_{\rm c}<10.4\,{\rm M_{\odot}}$. This indicates that at least some low-mass objects are forming coevally with more massive counterparts. Comparing to the popular "bead-on-a-string" analogy, the protocluster hub is poorly represented by a monolithic clump embedded within a single filament. Instead, it comprises multiple intra-hub filaments, each of which retains its integrity as an independent structure and possesses its own embedded core population

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

A separated vortex ring underlies the flight of the dandelion

Wind-dispersed plants have evolved ingenious ways to lift their seeds1,2. The common dandelion uses a bundle of drag-enhancing bristles (the pappus) that helps to keep their seeds aloft. This passive flight mechanism is highly effective, enabling seed dispersal over formidable distances3,4; however, the physics underpinning pappus-mediated flight remains unresolved. Here we visualized the flow around dandelion seeds, uncovering an extraordinary type of vortex. This vortex is a ring of recirculating fluid, which is detached owing to the flow passing through the pappus. We hypothesized that the circular disk-like geometry and the porosity of the pappus are the key design features that enable the formation of the separated vortex ring. The porosity gradient was surveyed using microfabricated disks, and a disk with a similar porosity was found to be able to recapitulate the flow behaviour of the pappus. The porosity of the dandelion pappus appears to be tuned precisely to stabilize the vortex, while maximizing aerodynamic loading and minimizing material requirements. The discovery of the separated vortex ring provides evidence of the existence of a new class of fluid behaviour around fluid-immersed bodies that may underlie locomotion, weight reduction and particle retention in biological and manmade structures

Clinical implications of serum neurofilament in newly diagnosed MS patients: a longitudinal multicentre cohort study

BACKGROUND: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. METHODS: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. FINDINGS: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels. INTERPRETATION: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions